title: A novel and comprehensive mouse model of human non-alcoholic steatohepatitis with the full range of dysmetabolic and histological abnormalities induced by gold thioglucose and a high-fat diet.
abstract: BACKGROUND
  The search for effective treatments of non-alcoholic steatohepatitis (NASH), now the most common chronic liver disease in affluent countries, is hindered by a lack of animal models having the range of anthropometric and pathophysiological features as human NASH.
  
  
  OBJECTIVE
  To examine if mice treated with gold thioglucose (GTG) - known to induce lesions in the ventromedial hypothalamus, leading to hyperphagia and obesity - and then fed a high-fat diet (HF) had a comprehensive histological and dysmetabolic phenotype resembling human NASH.
  
  
  METHODS
  C57BL/6 mice were injected intraperitoneally with GTG and then fed HF for 12 weeks (GTG+HF). The extent of abdominal adiposity was assayed by CT scanning. A glucose tolerance test and an insulin tolerance test were performed to evaluate insulin resistance (IR). Histological, molecular and biochemical analyses were also performed.
  
  
  RESULTS
  Gold thioglucose+HF induced dysmetabolism, with hyperphagia, obesity with increased abdominal adiposity, IR and consequent steatohepatitis, with hepatocyte ballooning, Mallory-Denk bodies, perivenular and pericellular fibrosis as seen in adult NASH, paralleled by an increased expression of the profibrogenic factors, transforming growth factor-β1 and TIMP-1. Plasma adiponectin and the expression of adiponectin receptor 1 and receptor 2 were decreased, while PPAR-γ and FAS were increased in the livers of GTG+HF mice. In addition, GTG+HF mice showed glucose intolerance and severe IR.
  
  
  CONCLUSIONS
  Treatment with GTG and HF diet induce, in mice, a comprehensive model of human NASH, with the full range of dysmetabolic and histological abnormalities.
authors.affiliation: Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi, Japan.
authors.forename: Mitsunari
authors.initials: M
authors.lastname: Ogasawara
authors.forename: Akira
authors.initials: A
authors.lastname: Hirose
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ono
authors.forename: Kosuke
authors.initials: K
authors.lastname: Aritake
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Nozaki
authors.forename: Masaya
authors.initials: M
authors.lastname: Takahashi
authors.forename: Nobuto
authors.initials: N
authors.lastname: Okamoto
authors.forename: Shuji
authors.initials: S
authors.lastname: Sakamoto
authors.forename: Shinji
authors.initials: S
authors.lastname: Iwasaki
authors.forename: Taketoshi
authors.initials: T
authors.lastname: Asanuma
authors.forename: Taketoshi
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Urade
authors.forename: Saburo
authors.initials: S
authors.lastname: Onishi
authors.forename: Toshiji
authors.initials: T
authors.lastname: Saibara
authors.forename: Jude A
authors.initials: JA
authors.lastname: Oben
mesh_terms: D052242:Adiponectin / Q000097:blood; D000273:Adipose Tissue / Q000000981:diagnostic imaging; D000818:Animals; D006051:Aurothioglucose / Q000008:administration & dosage / Q000633:toxicity*; D004041:Dietary Fats / Q000009:adverse effects*; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D005951:Glucose Tolerance Test; D007031:Hypothalamus / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D047495:PPAR gamma / Q000378:metabolism; D054419:Receptors, Adiponectin / Q000378:metabolism; D018709:Statistics, Nonparametric; D014057:Tomography, X-Ray Computed
chemical_list: D052242:Adiponectin; D004041:Dietary Fats; D047495:PPAR gamma; D054419:Receptors, Adiponectin; D006051:Aurothioglucose